The Tyrosine Kinase Inhibitor STI571 Induces Cellular Clearance of PrPSc in Prion-infected Cells

• Published in: The Journal of biological chemistry Vol. 279; no. 40; pp. 41918 - 41927
• Main Authors: Ertmer, Alexa, Gilch, Sabine, Yun, Seong-Wook, Flechsig, Eckhard, Klebl, Bert, Stein-Gerlach, Matthias, Klein, Michael A, Schätzl, Hermann M
• Format: Journal Article
• Language: English
• Published: United States American Society for Biochemistry and Molecular Biology 01.10.2004
• Subjects: Animals; Benzamides; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Enzyme Inhibitors - pharmacology; Imatinib Mesylate; Lysosomes - metabolism; Mice; Piperazines - pharmacology; Prion Diseases - drug therapy; Prion Diseases - pathology; Protein-Tyrosine Kinases - antagonists & inhibitors; Proto-Oncogene Proteins c-abl - antagonists & inhibitors; PrPSc Proteins - antagonists & inhibitors; PrPSc Proteins - drug effects; Pyrimidines - pharmacology; Signal Transduction - drug effects
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M405652200

The conversion of the cellular prion protein (PrP c ) into pathologic PrP Sc and the accumulation of aggregated PrP Sc are hallmarks of prion diseases. A variety of experimental approaches to interfere with prion conversion have been reported. Our interest was whether interference with intracellular signaling events has an impact on this conversion process. We screened ∼50 prototype inhibitors of specific signaling pathways in prion-infected cells for their capacity to affect prion conversion. The tyrosine kinase inhibitor STI571 was highly effective against PrP Sc propagation, with an IC 50 of ≤1 μ m . STI571 cleared prion-infected cells in a time- and dose-dependent manner from PrP Sc without influencing biogenesis, localization, or biochemical features of PrP c . Interestingly, this compound did not interfere with the de novo formation of PrP Sc but activated the lysosomal degradation of pre-existing PrP Sc , lowering the half-life of PrP Sc from ≥24 h to <9 h. Our data indicate that among the kinases known to be inhibited by STI571, c-Abl is likely responsible for the observed anti-prion effect. Taken together, we demonstrate that treatment with STI571 strongly activates the lysosomal degradation of PrP Sc and that substances specifically interfering with cellular signaling pathways might represent a novel class of anti-prion compounds.